1. Field of the Invention
The field of the invention is a novel crystal form of a known compound, linezolid which is pharmaceutically useful as an antibacterial agent.
2. Description of the Related Art
U.S. Pat. No. 5,688,792 discloses the antibacterial agent linezolid as well as a process for its preparation. EXAMPLE 5 reports the linezolid produced had a mp of 181.5-182.5xc2x0.
There are many other disclosures of processes to prepare linezolid. J. Med. Chem., 39(3), 673-9 (1996) reports the linezolid was, xe2x80x9crecrystallized from ethyl acetate and hexanes . . . white crystals, m.p. 181.5-182.5C.xe2x80x9d It also sets forth the IR spectrum as xe2x80x9c3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435xe2x80x9d.
Tetrahedron Lett., 40(26), 4855 (1999) discloses linezolid and a process to prepare linezolid. However, this document does not set forth the melting point or IR spectrum of the linezolid prepared.
U.S. Pat. No. 5,837,870 (International Publication WO97/37980 of PCT/US97/03458) discloses a process to prepare linezolid. Linezolid is described in EXAMPLE 18, which does not set forth the melting point or IR spectrum of the linezolid prepared.
International Publication WO99/24393 of PCT/US98/20934 discloses a process to prepare linezolid. Linezolid is described in EXAMPLES 8, 9 and 12 which do no set forth the melting point or IR spectrum of the linezolid prepared.
The form of linezolid being used in the clinical trials to support the filing of the NDA is Form II.
Disclosed is a (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal xe2x80x9cForm IIxe2x80x9d with a powder X-ray diffraction spectrum of:
Also disclosed is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal xe2x80x9cForm IIxe2x80x9d with an infrared (IR) spectrum as a mineral oil mull: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cmxe2x88x921.
Further disclosed is a process to prepare (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal xe2x80x9cForm II xe2x80x9d which comprises:
(1) producing (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide in greater than 98% enantiomeric purity,
(2) mixing the greater than 98% enantiomerically pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide in a solvent or mixture of solvents at a temperature below a temperature of about 80xc2x0 and
(3) separating the (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide crystal xe2x80x9cForm IIxe2x80x9d from the solvent(s).
Linezolid, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, is a known pharmaceutically useful antibacterial agent, see U.S. Pat. No. 5,688,792 (EXAMPLE 5). Linezolid can be used orally or given by IV as a sterile solution.
When linezolid was originally produced, the crystal form was Form I. Form II differs from Form I in its IR spectrum, X-ray powder diffraction spectrum and melting point.
Once linezolid is synthesized, crystal Form II is prepared by starting with linezolid of high enantiomeric purity. It is preferred that the linezolid be more than 98% enantiomerically pure, it is more preferred that the linezolid be more than 99% pure and it is even more preferred that the linezolid be 99.5% pure. The linezolid of greater than 98% enantiomeric purity to be used to form crystal form II can either be in solution or be a solid. The linezolid starting material, solid or solution, is mixed with a solvent selected from the group consisting of:
water,
acetonitrile,
chloroform, methylene chloride, toluene,
R1xe2x80x94OH where R1 is C1-C6 alkyl,
R1xe2x80x94COxe2x80x94R2 where R2 is C1-C6 alkyl or phenyl substituted with 1 thru 3 R1 where R1 is as defined above, and where R1 is as defined above,
R1xe2x80x94COxe2x80x94Oxe2x80x94R2 where R1 is C1-C6 alkyl and R1 is as defined above,
R1xe2x80x94Oxe2x80x94R2 where R1 is C1-C6 alkyl and R1 is as defined above. It is preferred that the solvent be selected from the group consisting of water, ethyl acetate, methanol, ethanol, propanol, i-propanol, butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, methylene chloride, toluene, xylene, diethyl ether, or methyl-t-butyl ether. It is more preferred that the solvent be ethyl acetate, acetone, acetonitrile, propanol, or isopropanol. It is most preferred that the solvent be ethyl acetate.
The mixture of linezolid in the solvent is agitated at a temperature below 80xc2x0 until crystals of Form II are formed and crystals of other solid forms, such as Form I, disappear. It is preferred to dissolve the linezolid in ethyl acetate at a temperature near the boiling point of the solvent. This mixture is cooled to a temperature of about 70xc2x0. The mixture may be seeded with crystals of Form II to facilitate crystallization. It is preferred that the solid product is cooled and agitated at a temperature between about 45xc2x0 and about 60xc2x0 until the solids consist only of Form II crystals. It is most preferred to maintain the slurry at a temperature of about 55xc2x0. It is preferred to mix the linezolid and solvent for at least 10 min, it is even more preferred to mix the linezolid and solvent for at least 20 min and it is most preferred to mix the linezolid and solvent for at least 30 min. The time and temperature will vary depending on the solvent selected. With ethyl acetate it is preferred to mix for not less that 60 minutes.
The crystalline slurry may be further cooled to improve yield, and the solid Form II product may be isolated. The mixture may be further cooled and agitated. Other measures which can be used to facilitate crystallization include, but are not limited to, cooling, concentration of the solution by evaporation or distillation, or through addition of other solvents.
The crystals are isolated by procedures known to those skilled in the art.
Crystal Form II is the most stable form below about 85xc2x0. It is preferred to use starting material with less than 0.2% of the R enantiomer of linezolid to minimize or eliminate the formation of a pseudoracemic solid solution of the two enantiomers which tends to crystallize as the Form I solid, even at temperatures below 85xc2x0.
It is well known to those skilled in the art that linezolid is useful as an antibacterial agent, see for example U.S. Pat. No. 5,688,792.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
Linezolid refers to (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide the compound of formula: 
All temperatures are in degrees Centigrade.
IR refers to infrared spectroscopy.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
The term C1-C6 alkyl means alkyl of 1 thru 6 carbon atoms and isomers thereof where such exist.